Lecithins, acetylated

Neurotoxicity

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: sub-chronic oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422

Deviations:

yes

Remarks:

Study included FOB and motor activity endpoints

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3650 (2000)

Deviations:

yes

Remarks:

Study included FOB and motor activity endpoints

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

All animals were dosed once daily by gavage for approximately 14 days prior to cohabitation and during the cohabitation period (up to 2 weeks). Male and female rats showing no evidence of copulation continued to be dosed after the end of the cohabitation period until sacrifice. Females showing evidence of copulation were dosed throughout gestation. Pregnant females in the process of delivery or showing signs of delivery were not dosed. Females were dosed after delivering litters, until day 3 postpartum. Females that did not deliver a litter continued to be dosed until the day before sacrifice.

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

12 animals/sex/dose

Control animals:

yes, concurrent vehicle

Neurobehavioural examinations performed and frequency:

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Pretest and near the end of the premating period
- Dose groups that were examined: All animals prior to dosing and at the end of the premating period
- Battery of functions tested: abbreviated functional observational battery (FOB) assessments and motor activity (MA). The FOB assessment included assessments of approach and touch, sharp auditory stimulus (e.g., clicker), tail pinch, forelimb grip strength, hindlimb grip strength, papillary constriction, polyuria, and diarrhoea. The motor activity monitors enabled the measurement of 2 dependent variables, duration or movement and number of movements.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Sex:

male/female

Remarks on result:

other: no effects at highest dose tested

Refer to Section 7.5.1 Repeated dose toxicity: oral: DI.K1.28Day.Gav.Screen.RD/REPRO/DEV.R.D-18511-1422.KD for additional details of repeated dose systemic toxicity findings. Refer to Section 7.8.1 Toxicity to reproduction: DI.K1.DEV.Screen.RD/REPRO/DEV.R.D-18511-1422.KD for reproductive toxicity findings. Refer to Section 7.8.2 Developmental toxicity/teratogenicity: DI.K1.DEV.Screen.RD/REPRO/DEV.R.D-18511-1422.KD for developmental toxicity findings.

Conclusions:

NOAEL = 1000 mg/kg

Executive summary:

The objective of this study was to evaluate the potential subchronic and reproductive/developmental toxicity of the test substance when administered by oral gavage to male and female rats during premating, cohabitation, gestation, until postnatal day (PND) 3. Four groups of parental (P₀) male and female Crl:CD(SD) rats (12/sex/group) were administered formulations of the test substance via once daily oral gavage for 14 consecutive days prior to mating, throughout mating, and then continuing through one day prior to the day of euthanasia. The dose levels administered were 0, 100, 300, or 1000 mg/kg/day. Samples of the dose formulations were analyzed and confirmed that the formulations were at targeted concentrations, homogeneous, and stable under the conditions of use.  During the in-life phase of the study, all animals were observed twice daily for appearance and behaviour. Clinical observations, body weights, and food consumption were recorded at appropriate intervals for P₀ males throughout the study and for P₀ females prior to mating and during gestation and lactation. Neurobehavioral examinations consisting of an abbreviated functional observational battery (FOB) and motor activity (MA) were performed for all P₀ animals once prior to dosing to provide baseline data and once more near the end of the premating period. In addition, clinical pathology data consisting of haematology, coagulation, and clinical chemistry data were collected prior to the end of the premating period. All P₀ females were allowed to deliver and rear their pups until weaning on PND 4. Each P₀ parental animal received a complete detailed gross necropsy and selected organs were weighed and/or retained for histopathologic examination.

 

There was no evidence of test substance-related toxicity at any dose level tested. The in-life data, including body weight and food consumption parameters, clinical observations, neurobehavioural endpoints (FOB and MA), clinical pathology, as well as reproductive performance data including mating and fertility indices, gestation length, offspring viability, litter sizes, litter sex ratio, and pup weights, were comparable across all groups throughout the study. In addition, there were no test substance-related effects on either gross or microscopic histopathology or on organ weights. 

 

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for neurotoxicity was 1000 mg/kg/day. This conclusion is based on the lack of any evidence of any adverse and/or test substance-related effects at any dose level tested.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

No effects on neurotoxicity (functional observational battery and motor activity) were observed in a repeated dose/one generation reproduction study (OECD 422), nor were any clinical signs suggestive of neurotoxicity observed in any other studies following acute exposure by oral, dermal, or inhalation routes of exposure.

Justification for classification or non-classification

Based on the lack of adverse effects on neurotoxicity at the highest dose tested (1000 mg/kg/day) in a repeated-dose toxicity study and the lack of evidence of neurotoxicity in acute toxicity studies, the test substance does not need to be classified for neurotoxicity or specific toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.